Viruses are considered the second most important cause of malignant disease in humans, contributing up to 14-20% of all cancers worldwide. Human cancers associated with virus infection include adult T-cell leukemia (ATLL- human T-cell lymphotropic virus infection; HTLV-1 infection), non-Hodgkins lymphoma (Epstein-Barr Virus; EBV infection) and kaposi's sarcoma (human herpes virus 8; HHV8 infection). A leading cause of death in HIV-infected individuals is also caused by malignant disease induced by selected viral infection. The University of Miami (UM) School of Medicine is in a unique position to study these increasingly prevalent malignant disorders. Essentially, Southern Florida is an endemic area for viral-associated cancers and has the largest cohorts of patients with such diseases in the world. Given this situation, we have assembled a team of investigators at the University of Miami School of Medicine, Sylvester Comprehensive Cancer Center (SCCC), UM, experts in their respective fields of viral oncology and the regulation of host defense. These are Glen N. Barber, Ph.D., William Harrington Jr., M.D., Enrique Mesri, Ph.D., and Ed Harhaj, Ph.D. All are members of the Viral Oncology Program, SCCC, co-headed by Professors Harrington and Barber. Our proposal focuses on overlapping strengths prevalent within our group and takes advantage of our expertise in analyzing host defense and the importance of the interferon (IFN) pathway in naturally combating viral and malignant disease. For example, we have recently elucidated a toll-independent arm of innate immune signaling, essential for the induction of IFN and subsequent expression of anti-viral and anti-tumor genes. These important signaling pathways now appear, unsurprisingly, to be targeted by a growing number of viruses, consequences that may explain mechanisms of viral resistance to IFN therapy, latency and speculatively tumorigenesis. Our proposal focuses on further studying innate immune signaling mechanisms critical for effective host defense. Our study also encompasses the regulation of these processes by the oncoviruses HTLV-1, HHV8 and EBV. More specifically, our proposal comprises three major components: PROJECT I, Glen N. Barber, Ph.D.: Mechanisms of host defense and regulation by oncoviral encoded gene products. PROJECT II, William Harrington, Jr., M.D.: Host Defense regulation by HTLV-1. PROJECT III, Enrique Mesri, Ph.D.: HHV8 (KSHV)-Mediated Regulation of Host Defense.